N‐acetylcarnosine (NAC) drops for age‐related cataract
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness of carnosine as a cataract‐reversing agent and as a preventative agent.
Background
Description of the condition
Cataract is opacification of the lens within the eye which can cause symptoms due to poor, or altered quality of vision. This can lead to a reduced ability to carry out activities of daily living, driving or working.
The latest figures show that cataract is responsible for 48% of world blindness, representing some 17.6 million people worldwide (Resnikoff 2004), making it the leading cause of blindness worldwide. There were 270,000 cataract operations carried out in the UK in 2002‐3. Both these sets of figures attest to the size of the problem and hence the number of people who may benefit from a freely available non‐surgical solution to symptomatic cataracts. This is especially relevant to countries with emerging economies, where the necessary expertise or equipment may not be readily available.
Description of the intervention
Anti‐cataract drops are instilled onto the affected eye twice a day. A course of treatment is recommended for a minimum of two months and may be required indefinitely to prevent progression of the cataract.
One of the causes of cataract is oxidative stress within the lens. Oxidative stress results in the formation of free radical species. Carnosine is a naturally occurring dipeptide implicated in reducing free radicals in the body.
Topical application of carnosine onto the ocular surface does not result in penetration into the eye. Hence, a vehicle has been developed, called N‐acetyl carnosine (NAC). NAC is instilled onto the eye and penetrates the anterior chamber of the eye through the cornea. Subsequent metabolism of NAC within the eye produces L‐carnosine, the active drug (Babizhayev 1996).
L‐carnosine has been shown to have an antioxidant effect on the cataractous lens (Babizhayev 1989). Consequently, it is possible that topical administration of NAC could lead to a reduction in cataract by either slowing down the progression of the cataract or indeed reversing the cataractous change.
NAC has been shown to improve best‐corrected visual acuity (Babizhayev 2002).
Why it is important to do this review
The current forms of management are either conservative or surgical. Conservative management consists of informing the patient that they have the condition, that it will worsen with time, but that the rate of decline is unpredictable. It may cause the patient to cease or downgrade certain activities such as driving, working or self‐caring. Conversely, it may never affect the patient if it is mild or the patient does not need good vision. Most of the time however, the patient presents to an ophthalmologist due to symptoms attributable to cataract.
The Royal College of Ophthalmology (UK) guidelines for surgical treatment consist of day case admission (i.e. not an overnight stay) for the vast majority of patients and involve a local anaesthetic (i.e. the patient remains awake through the procedure). Overall success rates quoted include 95% of patients being satisfied with the results of the surgery (Lum 2000), and the quoted risk of sight‐threatening infection is 0.1% (Montan 2002).
In developed countries a medical treatment or prophylactic agent would add to the treatment options available to the ophthalmologist and in the primary care setting: fewer patients would present to the ophthalmologist, and of those who did, fewer would require surgery; patients could choose which treatment option they prefer and fewer surgical complications would arise from fewer operations. In countries with emerging economies it may mean the difference between survival and death.
Objectives
To assess the effectiveness of carnosine as a cataract‐reversing agent and as a preventative agent.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised and quasi‐randomised controlled trials. We will exclude cross‐over trials due to the uncertainty regarding carry‐over.
Types of participants
We will include trials where participants are over 50 years of age with measurable cataract, as defined by a suitably qualified medical practitioner or researcher, which is shown to be affecting their quality of life through reduced or abnormal vision. We will not make any demographic differentiations. We will exclude participants with ocular comorbidity as this condition may make it difficult to diagnose the cause of reduced vision.
Types of interventions
We will include all trials where topical NAC is compared to a control (such as saline or artificial tear) or to cataract surgery. Included trials will have a minimum treatment period of two months.
Types of outcome measures
Primary outcomes
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Cataract appearance as defined on LOCS III grading slides or Scheimpflug photography (pixel counting).
We will assess the primary outcome as short‐term (less than one year) and long‐term (more than one year). Change will be as defined by the trial investigators.
Secondary outcomes
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Quality of life as measured by validated quality of life questionnaires, namely VCM1, IVI, VFQ‐25, AVL, Van Dijk, NHI, Carta, SQDL‐DVI, ADVS, VF‐14, VDA, CSS, TyPE, HVAT, MIOLS VFQOL, Catquest, Mone‐stam and VFI.
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Visual acuity as measured by Snellen (imperial or metric), LogMAR or ETDRS charts.
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Contrast sensitivity as measured by validated printed optotype or grating tests, namely Mentor B‐VAT, CSV‐1000, MCT 8000, Pelli‐Robson, ETDRS, Cambridge, Regan and Joyce.
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Glare disability as measured by validated glare disability tests, namely Mentor BAT, Miller‐Nadler and Berkely glare test.
We will assess all secondary outcomes as short‐term (less than one year) and long‐term (more than one year). Change will be as defined by the trial investigators.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There will be no date or language restrictions in the electronic searches for trials.
See Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), CINAHL (Appendix 4), AMED (Appendix 5 ), mRCT (Appendix 6) and ClinicalTrials.gov (Appendix 7).
Searching other resources
We will search the reference lists of included studies and search the Science Citation Index database to identify any additional trials. We will handsearch the Society meetings of the American Society of Cataract and Refractive Surgery and the European Society of Cataract and Refractive Surgery, from 2005 to the present.
Data collection and analysis
Selection of studies
Two authors (VD, AB) will search through the results. We will include studies on the basis of the criteria specified above. For studies that we have labelled as 'include' or 'unsure', we will obtain a full‐text report of the study. In the excluded studies table we will document any studies that we exclude at this stage. The two authors will resolve any disagreement by discussion.
Data extraction and management
We will design a paper data collection form. The form will consist of study and version ID, review author ID, citation and contact details, confirmation of eligibility for review, any reasons for exclusion of participants, study design, study duration, evidence of sequence generation and allocation sequence concealment, masking and documentation of any concerns over bias.
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Participant factors: number, setting, diagnostic criteria, age, sex, country and study dates.
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Intervention data: number of groups, number of participants per group and details of intervention for all groups.
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Outcomes: quality of life (differences in scores between baseline and study endpoint), cataract severity (differences in LOCS III scores and density (Scheimpflug) between baseline and study endpoint) and visual function (differences in measured visual acuity and contrast sensitivity between baseline and study endpoint).
We will collect these data at short‐term (less than one year) and at long‐term (more than one year) intervals. We will base the outcome criteria on change from the baseline; we will record scales, including limits and units of measurement.
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Results: any missing participants, summary data as detailed above including means, confidence intervals and P values.
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Adverse event data: (worsening in quality of life scores, visual function, or cataract within the study period, or adverse effects from topical application of NAC drops, i.e. pain, eye infection, allergy and scarring to ocular surface) and relevant notes.
We will document sources of funding, along with key conclusions from study authors, any references to related studies and any comments from the review authors.
Both authors will independently collect all the data. One author (VD) will enter the data from both authors into Review Manager 5 (RevMan 2011) and the second author (AB) will then check that the data have been correctly entered.
Assessment of risk of bias in included studies
We will use the Cochrane Collaboration's tool for assessing risk of bias as per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and assess the following: sequence generation, allocation concealment, masking of participants, incomplete outcome data, selective outcome reporting and other sources of bias. We will assess all parameters as "low", "high" or "unsure" risk of bias.
Measures of treatment effect
We will analyse ordinal data such as visual acuity and LOCS III grading as continuous data, using their respective standardised mean differences (SMDs).
We will analyse continuous data such as cataract density (measured by pixel counting on a Scheimpflug camera system) and quality of life data, with respective SMDs, as the measurement scales may vary depending upon which equipment or method(s) are used in each study.
We will consider data on glare sensitivity and contrast sensitivity as ordinal or continuous, depending upon the measurement method used.
Unit of analysis issues
We will exclude cross‐over trials due to the potential for carry‐over in this instance.
We will only include studies where people are randomised to treatment. We will exclude trials where one eye receives treatment and the other placebo.
Trialists may use two main methods to deal with the problem of non‐independence of data from eyes: (i) they may enrol one eye per person into the trial, or (ii) they may analyse data from both eyes adjusting the analyses for within‐person correlation.
For (i), we will document the criteria used to define which eye is to be included in the trial.
For (ii), if the trialist has not adjusted for within‐person correlation, we will take statistical advice.
Dealing with missing data
We will document the reasons why participants were not followed up, if reported. We will contact study trialists for further clarification as needed. At that stage we may be able to make judgements as to whether the data are missing at random or not. We will address the potential impact of missing data in the 'Discussion' section.
Assessment of heterogeneity
We will investigate heterogeneity by looking at the forest plots and statistical tests (Chi2 and the I2 statistic).
Assessment of reporting biases
We will use funnel plots to help in our assessment of bias as per Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011), though there may be too few studies to obtain meaningful interpretation from this tool.
Data synthesis
As we cannot assume that the intervention will have the same effect in different groups of people, that is, that each included study will be measuring the same effect, we will pool the data using a random‐effects model (providing there are three or more included trials providing relevant data). A random‐effects model will allow for differences in the effect of the intervention between the included trials. If the heterogeneity is too great, then meta‐analysis will not be possible.
Subgroup analysis and investigation of heterogeneity
We will consider the following subgroup analyses:
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smokers versus non‐smokers; and
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diabetics versus non‐diabetics.
